The primary goal of this project is to understand the molecular mechanisms responsible for genetically determined photoreceptor degeneration. The mouse mutants that undergo photoreceptor degeneration were chosen as a model system for study because of their similarity to human retinitis pigmentosa and their tractability to molecular genetic analysis. Four mouse mutants have been described (retinal degeneration (rd/rd), retinal degeneration slow (rds/rds), Purkinje cell degeneration (pcd/pcd) and nervous (nr/nr) in which photoreceptors undergo relatively normal development, but then subsequently degenerate. One aim of this proposal is to clone ten loci containing the genes: rd, rds, pcd and nr. The basic strategy involves the cloning a series of photoreceptor-specific mRNAs and then determining the chromosome- assignment for each gene. The analysis of clones corresponding to mRNAs encoded by genes that map to one of the four implicated chromosomes (5, 8, 13 and 17) will involve comparing the wild-type and mutant mRNAs, establishing tight linkage of a restriction fragment length polymorphism (RFLP) to the retinal degeneration phenotype, and fine-structure analysis of the locus. Final proof that the mutant gene has been cloned will require correcting the phenotype by introducing the wild-type allele into the homozygous mutant background in a transgenic experiment. Human homologs of mouse photoreceptor-specific mRNAs are candidate products of the retinitis pigmentosa loci. These clones will be used as probes to look for tightly linked RFLP'S between the DNA of normal humans and retinitis pigmentosa patients. This approach has the potential for cloning one or more of the retinitis pigmentosa loci. The most challenging aim of this proposal will be to characterize the protein products of ten retinal degeneration loci as they are cloned. If the protein is known, this analysis will be guided by the existing information. If the protein is novel, as appears to be the case for the rds gene product, the characterization will be more difficult but far more interesting.